Insulin maintains glucose homeostasis by several mechanisms: a) suppression of hepatic glucose production; b) stimulation of splanchnic (hepatic) glucose uptake and c) stimulation of peripheral (muscle) glucose (non oxidative) and oxidation. The precise contribution of each of these pathways to overall insulin-induced insulin-mediated glucose metabolism in awake chronically catheterized rats. Moreover, by quantitating hepatic glucose production, liver and skeletal muscle glycogen synthesis and whole body glycolysis during the insulin clamp study, I am able to evaluate the contribution of each of these pathways to the overall glucose disposal under different metabolic conditions. Recently, I have investigated the impact of the insulinomimetic agents, lithium and vanadate, on insulin- mediated glucose metabolism. Since these elements mimic some, but not all insulin effects, and do not directly bind to the insulin receptor, they can be used as experimental probes to better understand the intracellular mechanisms of insulin action. The results of these studies have allowed us to identify the metabolic pathways responsible for the impaired in vivo insulin action in a diabetic rat model. With these considerations in mind, I propose to combine the data obtained from the in vivo studies with in vitro analysis of tissue homogenates from the same animals in the attempt to identify the rate-limiting step(s) and the intracellular mechanism(s) responsible for the impairment of each metabolic pathway. The specific aims of the present proposal are: 1. To quantitate the contribution of different metabolic pathways to insulin-mediated glucose disposal in normal rats. 2. To identify the defective pathway(s) responsible for insulin resistance in diabetic rats. 3. To determine the rate-limiting step(s) of in vivo insulin action at different plasma insulin and glucose concentrations in normal and diabetic rats. 4. To delineate the influence of the route of the glucose administration on the pathways of glucose disposal in normal and diabetic rats. 5.To investigate the intracellular mechanism(s) of the lithium's and vanadate's insulinomimetic effects. 6.To quantitate modifications in enzyme activities following correction of hyperglycemia with different insulinomimetic agents.